A patent foramen ovale

A cause of poor oxygen delivery in CFS

The idea here is that if mitochondria go really slow, the heart does not beat strongly. This can result in an opening of the foramen ovale, a hole between the left and right atria (which normally closes as a flap at birth), so blood bypasses the lungs and does not pick up oxygen as it should. This means arterial oxygen levels will drop precipitously and CFSs suddenly dive into a much worse state. Please see Wikipedia:Foramen ovale (heart)

A Patent Foramen Ovale (PFO) (Mayo Clinic Discussion of PFO) therefore is a disease amplifying problem - it explains why some CFS sufferers get a lot worse with a relatively minor exertion, i.e. the degree of worsening is not commensurate with the effort.

The mechanism by which a PFO causes problems

Dr Paul Chaney explains one possible cause of poor oxygen delivery. For mitochondria to work they need a regular supply of oxygen. If oxygen levels fall, the mitochondria will go slow and acute fatigue (or even loss of consciousness) will result. One possible cause is a patent foramen ovale.

To explain this more fully we need to know a little bit about foetal life. During their development foetuses retrace our evolutionary pathway. Life developed in an atmosphere of very low oxygen tensions and a foetus has to do the same. During this time of life, excessive oxygen is highly damaging to foetuses and therefore they have to grow inside the body in the low oxygen tensions created in the womb. Indeed the oxygen tensions are equivalent to life at 29,000 feet! If an early foetus developed outside the body, it would quickly die from oxygen toxicity! The foetus gets its oxygen from the placenta - clearly it cannot get oxygen from its own lungs. Therefore blood is shunted within the heart from the right atrium to the left atrium through a hole in the heart called the foramen ovale. This is a flap valve, which bypasses the lungs. Everything changes at birth. At the baby’s first breath, the pressure in the lungs drops dramatically. This effectively sucks blood from the right ventricle, which sucks blood from the right atrium and the flap of flesh over the foramen ovale flops back and closes. In 72% of the population this flap seals up completely for life. In 28% of the normal population the flap does not seal up – it remains as a floppy flap. In normal circumstances this does not matter terribly because the pressure inside the left atrium is always higher than that in the right atrium and that pressure holds this flap shut. Problems arise when the pressure on the right side of the heart exceeds those on the left side and this flaps flops up and allows blood to shunt from right to left, so bypassing the lungs. Thus oxygen collection from the lungs is impaired because some blood does not get there.

It is surprising how little a pressure change is needed to open the floppy flap over the foramen ovale. When it has not stuck down, just valsalva manoeuvre will do it.(Valsalva manoeuvre is performed by a moderately forceful attempted exhalation against a closed airway, usually done by closing one's mouth, pinching one's nose shut while pressing out as if blowing up a balloon.) This would occur with sneezing, coughing, straining at stool, sleep apnoea and possibly snoring. I have one patient who gets severe headache with sneezing – this could be explained by a rush of poorly oxygenated blood into the brain.

CFS and PFO

The heart is particularly susceptible to this problem when it cannot beat strongly and is in a low output state. In this state, the blood pressure falls and the pressure difference between right and left is reduced further. We know this happens in patients with chronic fatigue syndrome and interestingly Dr Cheney has found that in chronic fatigue syndrome 90% of patients have a patent foramen ovale. Because the test for a PFO is not 100% reliable he believes that 100% of CFS patients have a PFO. However this only becomes a problem in low cardiac output states.

When the heart goes into a low output state it tries to increase cardiac output initially by the ventricle squeezing harder to empty more. However, when it relaxes, the elastic recoil sucks blood from the left atrium and causes left atrial cavitation, i.e. the left atrium collapses. If the foramen ovale is covered just by a flap, then blood could be sucked from the right atrium directly into the left ventricle. This means that blood does not circulate round the lung and therefore does not become oxygenated.

This, of course, would further impair the low cardiac output because oxygen levels in the blood fall so that oxygen supply to tissue is further impaired. Dr Cheney has demonstrated patent foramen ovale in 90% of patients using echocardiogram whilst patients do a Valsalva manoeuvre – he uses a technique called saline bubble test to visualise the blood within the chambers of the heart and can clearly see this shunting taking place. Interestingly this shunting has already been proven in cryptogenic ("unknown cause") migraine and probably explains why some migraine sufferers require high dose oxygen in order to recover. My guess is that this mechanism may well explain why some patients with multiple chemical sensitivity find they can relieve their symptoms with high dose oxygen. However, read on – for some people oxygen given like this makes them much worse!

PFO is known to be a cause of migraine, cryptogenic stroke (ie when the cause is unknown), decompression sickness, possibly obstructive sleep apnoea (because during this there is a valsalva like pressures when the sufferer attempts to breath against a closed glottis) and, Cheney reckons, 100% of CFSs.

Saline bubble tests for PFO

How Dr Cheney demostrates a PFO

For this test to be valid it has to be done properly. 10cc of saline is mixed with 1cc of air to create a froth – this is echogenic (ie Containing structures that reflect high-frequency sound waves and thus can be imaged by ultrasound techniques) and so it can be seen in ECHO cardiography (the bubbles are far too small to cause air embolism!). It must be injected into a leg vein so the bubbles appear in the right atrium from the inferior vena cava which sends a jet of blood directly at the flap covering the foramen ovale (injections into the arm result in a 30% false negative result because there is no such jet effect from the superior vena cava). The patient must then do a valsalva manoeuvre (increase pressure in chest as if straining at stool). The ECHO cardiogram clearly shows blood shunting from the right to the left side of the heart, through a PFO and so bypassing the lungs in 90% of CFS!

In patients with cryptogenic stroke one can see these bubbles clearly passing up into the brain when the patient does valsalva! If you are considering tests for a PFO, it is vital the cardiologist appreciates these points or you will get a high false negative rate.

Low cardiac output plus a PFO would explain POTs

Postural Orthostatic Tachycardia syndrome (POTs) occurs when a CFS sufferer stands for any length of time. During this time the heart is stressed (it is much harder work for the heart to circulate blood standing compared with lying down) and so output gradually falls. It suddenly gets to a critical state when the pressures fall on the left side of the heart, blood is shunted from the right side, the lungs are bypassed, oxygen tensions fall dramatically and unless the patient lies down quickly, he will go unconscious.

Does a PFO affect oxygen tolerance?

Cheney has shown that in some patients if the proportion of oxygen in air is increased from 21% to 28% this causes closure of the PFO, presumably because the heart can increase its output when there is more oxygen. However if oxygen is increased to 42% the PFO blows open again. Cheney thinks this is because too much oxygen cannot be handled biochemically, there is a rapid rise in free radicals which stop mitochondria working and so the heart output falls! This varies in different individuals but the point here is that oxygen is acting as a modulator. In CFS, Cheney reckons all patients have a PFO and all patients have oxygen toxicity in this way.

Depending on your antioxidant status (and most CFSs have poor antioxidant status) oxygen could make things better or worse!

CFS sufferers can have physiology like foetuses!

All foetusus have a PFO and oxygen is toxic to them. A foetus effectively lives at oxygen tensions of 29,000 feet! CFS patients effectively have mountain sickness. The reason why foetuses are like this is because they do not have the enzymes to protect them against oxygen stress namely superoxide dismutase, glutathione peroxidase and catalase – these enzymes are at 1/200th of adult levels.

CFSs have normal arterial blood gasses but venous gasses show low oxygen and high carbon dioxide. In CFS, the problem of oxygen delivery is further compounded because the red cells are “stiff” and cannot get through capillaries, meaning that circulation is slow. We now know this is because of high levels of malondialdehyde on red cell membranes due to oxidative stress. Please see Wikipedia article on malondialdehyde This oxidative stress results from poor antioxidant status – the body cannot deal with free radicals. I have certainly had one patient who has been made very much worse by a phospholipid intravenous infusion – my guess is that this suddenly caused the red cells to become more flexible, oxygen delivery was greatly improved and this caused massive pro-oxidant stress and tissue damage.

So oxidative stress will impair mitochondrial function and therefore cardiac output because free radicals impair mitochondrial biochemistry both directly and also indirectly through impaired oxygen delivery.

According to Cheney, all these observations point to oxygen and oxygen stress being a control point in chronic fatigue syndrome

Oxygen is clearly vital for efficient aerobic metabolism. It allows us, as human beings, to function at speed and this has massive evolutionary advantages. However, if we cannot handle oxygen this would result in massive pro-oxidant stress and we would quickly collapse and die. So what we actually do when we cannot handle oxygen is that we switch back into safe but slow anaerobic metabolism and hope that our body can repair its antioxidant defences quickly so that we can get back to normal life again. Almost certainly this is the mechanism of fatigue after any exertion whether that be the normal exertion of daily life, an acute illness, acute physical exertion, or whatever. Essentially if we cannot handle oxygen we switch back into safe, but slow anaerobic metabolism and effectively we mimic life as a foetus. As I say we have to do this because if we do not recover our antioxidant defences we die from oxygen toxicity! One example of how toxic oxygen can be – if you give 100% oxygen to a new born baby they will quickly go blind.

My clinical guess is that the symptom of fatigue is a symptom of poor anti-oxidant status and inability to deal with free radicals. The symptom of fatigue is a protective mechanism – it stops us doing things and so generating more free radicals from mitochondria until the antioxidant systems have recovered.

What causes this pro-oxidant stress?

The two major sources of free radicals in the body come from mitochondrial metabolism and the P450 detoxification enzyme system. One might think that mitochondria would produce a lot more free radicals than the P450 system because mitochondria are present in every single cell in the body. Interestingly it is the other way round – the P450 system produces many more free radicals. This may be because activity in mitochondria is tucked away within its own cell membrane and the rest of the cell relatively protected. Not so with the P450 detox system.

The P450 Detox system

The P450 detox system is present in every single cell of the body, but the most activity is found in the liver. About 40% of energy used by the liver supplies the P450 detox system – we need this in order to maintain a safe internal environment. Indeed the largest molecule in the body is catalase – 25% of all protein synthesis in the liver goes towards making this one enzyme – it is essential for mopping up the free radicals generated by P450 enzymes.

The P450 detox system is particularly active in human beings and the reason for this is that we eat a very wide range of foods, which are potentially toxic. We need our P450 literally to detoxify our diet. We eat kilograms of food daily which represent a vast, but obviously essential, toxic load. So long as we eat a Stone Age Diet, which does not alert the immune system excessively, we can cope with this comfortably. However, if we eat a toxic diet, which may be toxic because of allergies (immunotoxic), because of natural poisons in foods such as lectins, because of food additives, colourings or flavourings, or because of chemical residues or because of a fermenting gut, then we start to stress our P450 system. By stress, I mean that the free radicals generated overwhelm the antioxidant defences of P450. Indeed this explains nicely why chronic fatigue syndrome sufferers are so intolerant of alcohol (please see Alcohol intolerance in CFS - gives us a clue as to the mechanisms of fatigue) and much prescription medication – this provides yet another load on the P450 system which could result in an outburst of free radicals and pro-oxidant stress. Chemicals such as pesticides and heavy metals are toxic because they can further cause massive release of free radicals from this system.

Poor digestion of food, gut fermentation by yeast or bacteria, slow gut transit time would all increase the toxic load emanating from the gut. See Fermentation in the gut and CFS.

Mitochondria as a source of free radicals mopped up by SODase

One cannot burn sugar in the presence of oxygen to make ATP without producing free radicals. These are, largely speaking, superoxides. Think of them as hot exhaust gases which have to be cooled and detoxified by Superoxide dismutase (SODase) into water. This is achieved with incredible efficiency – one molecule of SODase will detox 100,000 free radicals in one second! Interestingly it achieves this by generating an electrical field and acting like an electrical fly trap. No wonder many people with CFS are electrically sensitive – this messes up the ability of their SODase to deal with free radical stress!

Having detoxified a free radical by removing an electron, this electron has to be moved on so that SODase can be reactivated – it does this by passing it on to second line antioxidants (such as vitamin E, vitamin K, bioflavanoids, vitamin D etc) who then pass the electron on to vitamin C – the ultimate repository! The whole chain has to be in place to work efficiently.

The antioxidant system

Antioxidants protect us from this free radical damage and there is no question that clinically improving antioxidant status is a central part of recovery in chronic fatigue syndromes. One of the most potent free radicals is peroxynitrite, which is formed when superoxides combine with nitric oxide. B12 is the most efficient scavenger of peroxynitrite and probably explains why it has such widespread application in fatigue syndromes – free radicals can be produced for any number of reasons from faulty mitochondrial function to allergies and chemicals causing free radical stress and therefore B12 has widespread appeal.

The main front-line antioxidant in the heart and circulation is glutathione peroxidase. Also see Antioxidants.

Possible Treatment Strategies

Firstly - address the symptoms.

This can make life more comfortable and that brings about benefits, but the main tool used by conventional medicine is medication and as we have seen, medication further stresses the P450 detox and can make the situation much worse. I think it is unlikely that cardiac surgery to treat the PFO will be helpful - it is the poor energy delivery to the heart that causes the problem and allows the PFO to blow open.

Secondly - address aetiology.

Since CFS is often triggered by viruses and chronic “stealth” infections are often blamed, antivirals, antibiotics and other such medications have been widely used. I have been generally unimpressed by results – indeed many patients are made much worse. This is a bit like treating lung cancer by stopping the patient smoking – the smoking has put in place a train of events which have a momentum of its own. However the key fact is that viruses attack the cooling system – get this right and the virus can be killed! To cause infection, viruses have to shift the redox state of their host in order to be able to replicate. If the redox state of the host is fine, then the virus is quickly killed. However if they are too successful in over-attacking the cooling system then their host (you and me) will die from free radical stress. Viruses have to hit the right balance! Too much and the host does not survive and if the host does not survive, the virus does not survive.

This explains why we all get exposed to viruses but not everyone is equally affected – it partly depends on your redox state as to how efficiently you deal with the virus.

This means that if the CFSs can shift his redox state in his favour, he will stop viral/pathogen replication. Indeed we already know this is the case with HIV infection!

However I do have a few patients (and it is just a few) who despite doing all the above to the letter, and having demonstrably normal mitochondrial function tests, improved antioxidant status, quality sleep etc continue with their CFS. But despite this they continue to have marked push/crash problems. This is what Cheney calls stage III maladapted stage.

Stage III CFS: the maladapted stage

Cheney believes that this third and maladapted stage of chronic fatigue syndrome arises because of abnormal control mechanisms. Normally in a stress situation there is a release of stress hormones from the thyroid gland, the adrenal gland, the pituitary gland in the brain and so on. Dr Cheney has been looking at the heart response when these hormones are applied to controls and to patients with fatigue syndromes. He has developed extracts of these tissues and applies them transdermally. He sees a response in the heart within 30 seconds. This alone is quite astonishing! What he finds is that when he applies these extracts to normal people, the heart improves its function. However, when he applies these extracts to patients with chronic fatigue syndrome the heart response invariably gets worse.

Cheney ran a trial whereby he took patients with CFS and for six months gave them transdermal liver extracts. Liver is rich in SODase and catalase. Although they improved with the heart tests, clinically they were no better. It was only when he added a heart extract, rich in glutathione peroxidase, that he saw clinical improvements. What Cheney was doing here I believe was to improve antioxidant status. Cheney thinks he was using these as “cell signalling factors” and believes this may be a way of reversing this “flip” in the HPA axis.

I am not sure how to interpret this observation because we are already improving SODase and glutathione peroxidase with nutritional supplements – the only issue we have not looked at directly is catalase and I will ask John McLaren Howard about this! From an evolutionary perspective, the tissues, which have always been prized by primitive societies and wild animals, are the offal meats – heart, liver, kidney etc - over and above muscle meat. Certainly primitive societies are much wiser than us when it comes to food choices!

Perhaps this is where psychological techniques could be helpful on CFS?

What Cheney is hypothesising from this is that the control mechanisms for chronic fatigue syndrome have flipped. Instead of hormones improving efficiency and function of the heart, when you have a chronic fatigue syndrome they do the opposite. This has to be a protective mechanism. This is where the psychological techniques may be helpful. There is no doubt that these do help some people, but they have the potential to make many worse. The question is why? The key is patient selection. I would argue that psychological techniques can never help people with proven physical lesions! But there will be some people who will have healed physically but their brain does not believe it – and continues to control energy levels. Please see Craig Robinson's chapter in my CFS book, and in particular pages 200-201, located here Catastrophe theory and CFS

The brain is constantly monitoring energy available to the body. Endurance athletes do this brilliantly well! There is a lovely story which illustrates this point as reported in New Scientist magazine. A runner who was also a sport’s psychologist, was competing in a marathon and had been told that the entire race was on the flat. At 18 miles he was running comfortably. He came round a corner and suddenly realised he had a mountain to climb. Within a millisecond of appreciating this, he felt the most over-whelming fatigue so he could barely walk and really struggled to complete the course! This cannot be explained by physical mechanisms – the brain suddenly realised there was much more to be done than had been previously appreciated and shut down the system to a level where completion was possible but at a much slower rate.

The brain is wired to learn – it does so by association and experience. Interestingly the NMDA receptor is central to the learning process and we know this is activated in inflammation and pro-oxidant stress.

It is important to realise that CFS is a protective adaptive state. If one did not switch into a CFS state, then the uncontrolled free radical stress would kill you! Just complete lack of sleep for 2 weeks is sufficient! If we force the system against its will, we risk creating more free radicals and making things much worse!

So we have some good questions! What are the answers? I don’t know!

What is the treatment for patent foramen ovale?

Probably not cardiac surgery! Phew! The PFO occurs in response to redox stress, 28% of normal people have PFO and do not have CFS!

Can we find an easy test for PFO?

How do we know when someone is in stage III and therefore it is safe to try a psychological treatment?

it would be very nice to have an objective test! Presumably in stage III, one’s redox state is that of a normal person. Can we find an easy test for redox state?

But what we do know is that all the therapies we are using have an excellent logical basis: Vis:

Reduce generation of free radicals

Rest and pacing

Low toxin diet

Get rid of toxins such as pesticides, heavy metals, VOCs and drug medication all of which are excellent at generating free radicals

Feedback from Dr John McLaren Howard

Redox state is greatly affected by pH (massive change in oxidation/reduction balance for small change in pH). This is particularly true when major components of the redox system are heavily protein-buffered. In CFS patients, the degree to which they switch to anaerobic metabolism is one of the major factors. Those who 'struggle on regardless' soon begin to depend on anaerobic mechanisms and build tolerance to increased lactate (acidosis). This has to be a major stress factor on general and cell-specific redox balance.

In the leucocyte respiration studies, we also see another major factor is electron transport/oxidative phosphorylation is uncoupled.

Catalase – this is a very interesting area and I have been trying to sort out a way of assessing it that throws light on the sort of mechanisms 'we' explore. There is so much of it, that it is not difficult to measure but rather just difficult to interpret any findings. One thing to keep in mind is that catalase 'reduces' organic forms of metals (including some detoxification conjugates) back to simple organic forms of the metals. This is a real problem in some cases because the inorganic - non fat soluble form cannot then escape the cell.

There is so much catalase in cells that this process is inevitable - at least for some toxic metals. As with increases in intracellular calcium, if it promotes apoptosis (ie the regulated cell suicide process known as programmed cell death) then at least the normal cell replacement cycle can continue. However, in some CFS patients we now know that calcium-binding proteins are induced as Ca-Actin binding increases. Please see Wikipedia article on Actin. If that happens with heavy metals then even more damage is possible and normal cell-replacement is not promoted because apoptosis is inhibited (not triggered is a better way of putting it).

The high affinity cation binding site of actin that I have investigated extensively re the intracellular calcium problem, is capable of binding a wide range of metals - it has been investigated in terms of cadmium toxicity for example. Once you have my write up on this (it's almost ready and gives full referenced details of the whole process of exploring the i/c Ca issue and Ca-Actin binding) you will see how significant this may be. Not in terms of calcium but for the toxic metals, catalase may be worsening the situation to a very great degree.

Back to redox issues, I am at an early stage in looking at a method that uses the instrumentation I use for leucocyte respiration parameters (Strathkelvin microrespirometry system) to see if I can get a meaningful handle on redox issues re CFS. Watch this space.